PROJECT SUMMARY (Overall Core: Maier and Zhang) The University of Arizona Superfund Research program (UA SRP) addresses the unique human health risks encountered in the US Southwest, an area with a rich history and future of mining. The Southwest has distinct geologic and climatic attributes that affect human health and exposures to pollution. Groundwater in Southwest regions with rich ore deposits often has elevated arsenic levels, leading to exposure from drinking water. Exposure also occurs by inhalation and ingestion of arsenic-associated mining dusts transported from mining sites into the interior of homes and to exterior environments. Importantly, arsenic exposure has been linked to the development of diabetes. Vulnerable populations residing near mining sites, including Native Americans and Hispanic communities, exhibit increased incidence of diabetes. Our goal is to determine how chronic exposure to mine wastes that contain arsenic contributes to the development of diabetes. We will then use this information to help predict exposures and associated health outcomes as well as to inform public health prevention strategies in communities that neighbor mine waste sites. To achieve this goal, we have five research projects and four cores that will: 1) characterize how chronic mine waste arsenic exposure in mining impacted areas is linked to diabetogenic outcomes through mediation of Nrf2 signaling; 2) determine how the gut microbiome and mining waste mineral properties influence arsenic species transformation, bioavailability, and toxicity; 3) investigate the influence of capping material quality on success of mine waste revegetation to enhance cap and plant remediation technology; 4) model exposures to mining waste contaminants, accounting for socio-demographics, to understand risk factors that drive development of diabetes; 5) mitigate the human impacts of exposure to mining waste through effective interaction with stakeholders including regulators, the mining industry, and affected communities; 6) serve as a global resource for human and environmental health issues associated with metal mining; and 7) train and graduate professionals who are equipped to address complex 21st century environmental hazardous waste problems (Aim 7). The expected outcome of this UA SRP effort is a measurable reduction in diabetes (and other diseases) in mining communities and perhaps beyond.